The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China.
FASEB J. 2024 Jul 31;38(14):e23833. doi: 10.1096/fj.202400972R.
Recurrent spontaneous abortion (RSA) is a common pregnancy-related disorder. Cbl proto-oncogene like 1 (CBLL1) is an E3 ubiquitin ligase, which has been reported to vary with the menstrual cycle in the endometrium. However, whether CBLL1 is involved in the occurrence and development of RSA remains unclear. This study aimed to investigate the effects of CBLL1 on RSA. We analyzed the expression of CBLL1 in the decidua of RSA patients, as well as its functional effects on cellular senescence, oxidative stress, and proliferation of human endometrial stromal cells (HESCs). RNA sequencing was employed to identify a key downstream target gene regulated by CBLL1. We found that CBLL1 was upregulated in the decidua of RSA patients. Additionally, overexpression of CBLL1 promoted HESC senescence, increased oxidative stress levels, and inhibited proliferation. Phosphatase and tensin homolog located on chromosome 10 (PTEN) was identified as one of the important downstream target genes of CBLL1. In vivo experiments demonstrated that CBLL1 overexpression in the endometrium caused higher embryo absorption rate in mice. Consequently, elevated CBLL1 expression is a potential cause of RSA, representing a novel therapeutic target for RSA.
复发性自然流产（RSA）是一种常见的妊娠相关疾病。Cbl 原癌基因样 1（CBLL1）是一种 E3 泛素连接酶，据报道其在子宫内膜中随月经周期而变化。然而，CBLL1 是否参与 RSA 的发生和发展尚不清楚。本研究旨在探讨 CBLL1 对 RSA 的影响。我们分析了 RSA 患者蜕膜中 CBLL1 的表达及其对人子宫内膜基质细胞（HESC）细胞衰老、氧化应激和增殖的功能影响。采用 RNA 测序鉴定 CBLL1 调控的关键下游靶基因。我们发现 CBLL1 在 RSA 患者的蜕膜中上调。此外，CBLL1 的过表达促进 HESC 衰老，增加氧化应激水平，并抑制增殖。位于 10 号染色体上的磷酸酶和张力蛋白同源物（PTEN）被鉴定为 CBLL1 的重要下游靶基因之一。体内实验表明，子宫内膜中 CBLL1 的过表达导致小鼠胚胎吸收率升高。因此，CBLL1 表达升高可能是 RSA 的一个潜在原因，为 RSA 提供了一个新的治疗靶点。
